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Published on: February 6, 2019
An integrated analysis of three medulloblastoma clinical trials refines risk-stratification approaches for reducing
Authors Kyle S Smith1,2, Sandeep K Dhanda3, Catherine A Billups4
1Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis (K.S.S., P.A.N.).
Background:
The identification of clinical and molecular heterogeneity in medulloblastoma has produced risk-stratified therapy, but establishing the most effective yet least toxic regimens has remained elusive owing to numerous treatment options. To improve risk-stratification, we performed an integrated analysis from three clinical trials.
Methods:
Medulloblastoma patients from ACNS0331/NCT00085735, ACNS0332/NCT00392327, and SJMB03/NCT00085202 were included if they had methylation profiling. Molecular groups [WNT, SHH, Group 3 (G3), and Group 4 (G4)], subgroups, and copy number variations were procured from methylation profiles and mutations from next-generation sequencing. Data was assembled into an interactive portal to capture patient characteristics. Cross-trial comparisons, univariable, and multivariable analyses were conducted and used to derive a risk-stratification schema.
Results:
Eight hundred ninety-eight patients (WNT = 131, SHH = 151, G3 = 220, G4 = 396) were included. Progression-free-survival (PFS) distributions among analogous cross-trial cohorts were not different, demonstrating no survival advantage of any one therapy over another. The addition of carboplatin to high-dose craniospinal irradiation (HDCSI) containing regimen was selectively superior in PFS in G3/G4 subgroup 3 (P = 0.048) and G3/G4 subgroup 2 (P = 0.035) to HDCSI regimens without carboplatin. Nine actionable risk-stratified groups were identified consisting of 2 WNT groups (low, high-risk), 3 SHH groups (low-, average-, very-high-risk), and 4 G3/G4 groups (low-, average-, high-, and very-high-risk).
Conclusions:
Our integrated cross-trial analysis suggests toxicity can be reduced by eliminating disproportionate differences in therapy in favor of a more uniform treatment backbone. Moreover, we propose and model a risk-classification system that identifies the most appropriate cohorts on which to trial significant dose reductions in craniospinal irradiation or select treatment intensifications.
Insights
This study integrated data from three medulloblastoma trials to refine risk stratification. A new classification system was developed to guide treatment, potentially reducing toxicity and improving outcomes for pediatric cancer patients.
Area of Science:
- Pediatric Oncology
- Neuro-Oncology
- Genomic Medicine
Background:
- Medulloblastoma exhibits clinical and molecular heterogeneity, necessitating risk-stratified therapies.
- Current treatment regimens face challenges in balancing efficacy with toxicity due to numerous options.
- Integrated analysis across multiple clinical trials is crucial for improving risk stratification.
Purpose of the Study:
- To perform an integrated analysis of data from three clinical trials to improve medulloblastoma risk stratification.
- To identify molecular subgroups and genetic alterations influencing treatment response.
- To develop a refined risk-classification system for medulloblastoma patients.
Main Methods:
- Included 898 medulloblastoma patients from ACNS0331, ACNS0332, and SJMB03 trials with methylation profiling.
- Utilized methylation profiles for molecular grouping (WNT, SHH, G3, G4) and next-generation sequencing for mutations.
- Conducted cross-trial comparisons and statistical analyses to derive a risk-stratification schema.
Main Results:
- No significant progression-free survival (PFS) advantage was found among analogous cross-trial cohorts.
- Carboplatin addition to high-dose craniospinal irradiation (HDCSI) improved PFS in specific G3/G4 subgroups.
- Identified nine actionable risk-stratified groups across WNT, SHH, and G3/G4 molecular medulloblastoma categories.
Conclusions:
- Integrated analysis suggests a uniform treatment backbone can reduce toxicity.
- A proposed risk-classification system aids in identifying patient cohorts for treatment de-escalation or intensification.
- This approach aims to optimize therapeutic strategies for medulloblastoma, balancing efficacy and safety.
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